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Jean-Louis Reymond

Synthetic molecules with targeted functions are in strong demand to study and manipulate biological phenomena. However the number and diversity of the molecules so far investigated in biology is insignificant compared to the universe of possibilities offered by synthetic chemistry. Access to a broader molecular diversity serving biology can be facilitated by clever design and synthesis of focused compound libraries.

In the 1990’s and early 2000’s our group designed fluorescent probes for enzymes to serve research in biocatalysis, which concerns the use of enzymes as clean and environmentally friendly catalysts for chemical manufacturing. We expanded the range of reaction types accessible to fluorescence screening by designing substrates with innovative activation mechanisms, allowing directed evolution and the discovery of new enzymes.

We also made improvements in assay systems for important enzyme classes such as lipases and proteases addressing selectivity problems. Many of our assays have become part of the standard arsenal of enzyme screening methods.

Since 2002 the group has entered the field of combinatorial peptide chemistry. Most biologically active molecules are linear or cyclic peptides. We have shown that peptide synthesis can be expanded to prepare ramified peptides, called peptide dendrimers, by incorporating branching points along the sequence. Peptide dendrimers adopt a globular protein-like conformation without folding, are resistant to proteolysis, and display useful functions such as catalysis, binding, cell targeting, or biofilm disrupting properties.

We have developed efficient functional screening and decoding methods that allow us to work with combinatorial libraries of tens of thousands of dendrimers on solid support.

The ultimate structural diversity of organic molecules lies not in the combinations of various building blocks as in peptides, but in the topology and types of chemical bonds between atoms. To access this diversity directly, we have entered the world of virtual chemistry and computed a database enumerating exhaustively all the organic molecules that are theoretically possible following simple rules of chemical stability and synthetic feasibility.

This database, called GDB (www.gdb.unibe.ch), has become an important resource for de novo compound design, in particular in the area of fragment based lead discovery. In analogy to the periodic system used to understand the diversity of chemical elements, we have recently proposed a general classification system for organic molecules based on Molecular Quantum Numbers (MQNs), which allows a direct visualization of chemical space and facilitates its exploration in the perspective of drug discovery.

Currently, we are pursuing a number of small molecule drug discovery projects by exploiting virtual screening schemes for searching very large compound databases, for example in the framework of the NCCR TransCure project.